Certain functionalized congeners of 1,3-dialkylxanthine exhibit high potency and selectivity as antagonists for A.sub.1 - and A.sub.2 -adenosine receptors and are suitable for attachment to probes, drug carriers, or solid supports. These derivatives are characterized by the presence of a phenyl substituent at the 8 position para-substituted with a functionalized chain to provide high water solubility and high receptor affinity to such an extent that these compounds are suitable for use as antiallergenic, antiasthmatic, or cardiotonic drugs, central nervous system stimulants, and diuretics.
Alkylxanthines, of which theophylline is the most well known, represent a major class of antagonists for adenosine receptors. Although theophylline and other xanthines such as caffeine are relatively weak adenosine antagonists, with affinity constants in the 10-50 micromolar range, they owe many of their pharmacological effects to blockage of adenosine mediated functions at the A.sub.1 and A.sub.2 receptor sites noted above. The A.sub.1 -adenosine receptor is inhibitory to adenylate cyclase and appears involved in antilipolytic, cardiac, and central depressant effects of adenosine. The A.sub.2 -adenosine receptor is stimulatory to adenylate cyclase and is involved in hypotensive, antithrombotic, and endocrine effects of adenosine. Some xanthines, such as 3-isobutyl-1-methylxanthine, not only block adenosine receptors but also have potent inhibitory effects on phosphodiesterases. In an effort to identify highly potent and specific analogs of adenosine receptor antagonists (xanthines) the functionalized "congener approach" was applied, as described in Jacobson et al, J. Med. Chem., 1983, Vol. 26, p. 492. Analogs of adenosine receptor ligands bearing functionalized chains are synthesized and covalently attached to various organic moieties, such as amines and peptides. The binding affinities (competitive CHA binding on rat cerebral cortex) and the specificity are modulated by changes in the attached moiety. The present invention discloses that the presence of a functionalized chain linked to the 8-phenyl group through a --O--CH.sub.2 CO-- linkage greatly enhances the potency of 1,3-dialkylxanthines as adenosine antagonists. Potent antagonists are produced by replacing the 1,3-methyl groups of 8-phenyltheophylline with n-propyl groups and by situating uncharged electron-donating para-substituents on the 8-phenyl ring. Amino acid conjugates are synthesized in which an amino acid "carrier" is linked through an amide bond to a functionalized xanthine congener. In addition to high potency, some of these 1,3-dipropyl-8-phenylxanthine derivatives exhibit selectivity toward either the A.sub.1 - or A.sub.2 -subclass of adenosine receptors. The amino congeners, in particular, exhibit improved water solubility and partition characteristics, permitting in vivo use of these congeners.
Many of the xanthines (such as theophylline) exhibit undesirable side-effects, such as cardiac stimulation. The present invention avoids or reduces these side-effects by developing compounds that are more potent or selective adenosine receptor blockers.
Furthermore, the A.sub.1 -specific antagonists, such as compound 6d, are useful therapeutically in combination with a non-specific adenosine agonist. The net effect of such a combination is decreasing blood pressure (an A.sub.2 effect of the agonist) without a concomitant effect on the heart rate (since the A.sub.1 -agonist effect of slowing the heart rate would be cancelled by the specific antagonist).
In the design of active covalent conjugates of drugs, the goals of the congener approach are several, including targeting, increasing the potency, prolonging the duration of action, and/or changing the specificity, and prodrugs. As noted above, they are useful therapeutically as antiasthmatic and antiallergenic drugs. Non-therapeutic applications of these active functionalized drugs include receptor probes, immobilized ligands for affinity chromatography, and radiolabeled analogs.
A further benefit of applying the congener approach to xanthines is the opportunity to increase water solubility. The series of super-active 8-phenylxanthines [PNAS, Vol. 80, p. 2077 (1983)] is highly non-polar with aqueous solubility very often falling below 10 micromolar, see Acta Physiol. Scand., Vol. 122, pp 191-198 (1984). By increasing water solubility through the attachment of highly polar charged or uncharged groups at positions which are also favorable to potency as adenosine antagonists, it is possible to overcome undesirable binding to plasma proteins and partition into lipids. This leads to improved pharmacokinetics of the drugs.
Some similar known compounds, such as the 8-arylxanthines, contain up to four substituents on the phenyl ring. These substituents usually contribute to the compound's insolubility in water. The present invention not only discloses a single substituent on the phenyl ring, it also discloses a variety of charged and uncharged hydrophilic substituents attached to xanthine through a functionalized chain. The combination of nanomolar potency and water solubility (concentrations approximately 10,000-fold greater than the receptor affinity constants) in the compounds of the present invention indicate high potency plus increased absorption.